Injectable Preparations Of Diclofenac And Its Pharmaceutically Acceptable Salts

ABSTRACT

The present invention provides injectable formulations of water-soluble salts of diclofenac in single doses of less than 2 ml, which cause significantly less pain at the site of injection and can be administered by intradeltoid route, in addition to intragluteal and slow intravenous route. More specifically the injectable preparations contain 75 mg to 100 mg of water-soluble salts of diclofenac, in about 1 ml injection solution without significantly raising the viscosity of the injection solution without the use surfactants. The formulations are adjusted to pH 6 to 10 containing up to 100 mg of diclofenac salt in a medium comprising of water, along with one or more co-solvent(s)/solubiliser(s), antioxidants, preservatives, buffers, alkali and stabilizers.

FIELD OF THE INVENTION

The present invention relates to high concentration preparations ofinjectable diclofenac salts that are capable of being administered byintradeltoid route, over and above the intragluteal and slow intravenousroute.

BACKGROUND AND PRIOR ART

Diclofenac is used, most commonly, as the Sodium or Potassium salt forrelief from pain and inflammation such as Musculoskeletal and jointdisorders including rheumatoid arthritis, osteoarthritis, and ankylosingspondylitis. It is also useful in peri-articular disorders such as renalcolic, acute gout, dysmenorrhea following surgical procedures. It hasalso been used in some countries for the management of fever.

British National Formulary recommends intramuscular injection into thegluteal muscle. Likewise, Martindale, the Extrapharmacopoea recommendsintragluteal injections. The other route of administration, recommendedis by IV infusion.

A typical parenteral administration is prepared by suspending ordissolving Sodium/Potassium salt of diclofenac in a non-toxic aqueous oroleaginous medium liquid vehicle.

Diclofenac injections have to be administered deep intramuscularly andare generally administered intragluteally as the injection causessubstantial pain at the site of injection and its administration in thedeltoid (upper arm) region is generally avoided.

Pain at the site of injection is due to relatively large volume of theinjection (3 ml) and the fact that the injection solution containsrelatively high volumes of propylene glycol, which is a known irritantupon parenteral administration. As mentioned in Applied NursingResearch, Vol. 16, No. 2, August, 2002 empirical data from publishedresearch reports, recommendations of established advisory panels andgenerally accepted scientific principals conclude that only smallvolumes of medication (2 ml or less) should be given in the deltoidsite. In fact, according to Nursing, January 1997, page 62-63,recommends the use of deltoid muscle only for volumes of 1 ml or less.

On the other hand intramuscular injection volumes above 2 ml and up to 5ml must be administered into the gluteal muscle (Applied NursingResearch, Vol. 16, No. 2, August, 2002). This is because; the glutealmuscle is larger as compared to the deltoid muscle and hence canaccommodate the relatively larger injected volume (3-5 ml) On the otherhand if this relatively larger volume is injected into the deltoidmuscles which has relatively lesser muscle mass, the injected solutionwill cause excessive stretching of the muscle fiber, thereby damagingthe local muscle tissue and hence cause pain and discomfort to thepatient. (Svendsen and Blom, Arch. Toxicol, Suppl. 7, 1984)

Further, injectable diclofenac preparations contain relatively highamounts (18-40%) of propylene glycol, which is a known irritant. TheExtra Pharmacopoeia 28^(th) edition, Hand book of excipients, furtherreports that aqueous solution of 2% propylene glycol iso-osmotic withserum causes 100% haemolysis of erythrocytes in 45 min. (Martindale, theExtrapharmacopoea 28th Edition)

Formulators have attempted to eliminate propylene glycol from theformulation in order to minimize pain at the site of the injection. Itmust be however be appreciated that the total volume of the injectionsolution plays a very significant role in addition to the amount ofpropylene glycol in the cause of pain at the site of the injection. Asmentioned above, the volume of the injected solution causes stretchingof the muscle fiber, and the higher the volume, more is the damage tothe local muscle tissue and hence pain and discomfort at the site ofinjection.

U.S. Pat. No. 3,558,690 discloses injectable preparations comprisingwater soluble salts of substituted phenyl acetic acid derivatives(diclofenac being one such compound) in concentrations of 0.5 to 5%

Conventional diclofenac injections marketed as single dose ampoules,contain 75 mg diclofenac sodium in 3 ml aqueous solution (2.5%). Multidose vials (30 ml) contain 750 mg in 30 ml solution (10 doses) are alsobeing marketed.

PCT application number WO 9603121 A1 describes a antiphlogistic,analgesic, antipyretic parenteral preparation comprising diclofenac, itssalt, or both, a surfactant, co-surfactant, water, at pH of 3-10 andoptionally comprising an oily component, that can exhibit sustainedtherapeutic levels of diclofenac in plasma and which does not cause painat site of injection.

U.S. Pat. No. 5,554,650 discloses an antiphlogistic, analgesic,antipyretic parenteral preparation that can exhibit sustainedtherapeutic levels of diclofenac in plasma comprising diclofenac, itssalt, or both, a surfactant, co-surfactant, water, adjusted to pH of3-10 and optionally comprising an oily component. Some preparationsclaim not to cause pain at site of injection since they excludepropylene glycol and instead use a surfactant and co-surfactant or oilwith surfactant and co surfactant to dissolve the diclofenac.

European Patent Application number 0658347 A3 describes a method ofpreparing an injectable pharmaceutical or veterinary composition, whichcomprises either diclofenac or a salt thereof, and 2 hydroxypropylbetacyclodextrin, or an inclusion complex of diclofenac or a saltthereof and 2 hydorxypropyle betacyclodextrin. Propylene glycol isexcluded and solubilisation effected with the help of 2 hydroxypropylbetacyclodextrin.

The present inventions attempts to provide preparations of concentratedsolutions of water soluble salts of diclofenac and reducing the overallvolume of injection to 1 ml resulting in the minimization of pain atsite of injection. Further, smaller volume enables administration in thedeltoid muscle.

While incorporating 75-100 mg of water-soluble salts of diclofenac andreducing the volume of the injection solution from 3 ml to 1 ml, theviscosity of the injection solution can rise thereby hampering the easeof administration of the injection. It is therefore important to makejudicious use of co-solvents/solubilisers, along with water, toformulate injection solutions of water-soluble salts of diclofenac, toprovide 75 mg to 100 mg in about 1 ml without substantially increasingthe viscosity. Further It is also desirable to provide injectablepreparations with low content of co-solvents/solubilisers to minimizetheir side effects.

OBJECTS OF THE INVENTION

The main object of the invention is to provide injectable formulationsof water-soluble salts of diclofenac, which cause significantly lesspain at the site of injection and can be administered by intradeltoidroute, in addition to intragluteal and slow intravenous route.

Another object of the invention is to provide single doses of less than2 ml

It is yet another object of the invention to provide injectablepreparations containing 75 mg to 100 mg of water-soluble salts ofdiclofenac, in about 1 ml injection solution.

It is yet another object of the invention to provide a full therapeuticdose of 75 mg to 100 mg of water-soluble salts of diclofenac in just oneml, without significantly raising the viscosity of the injectionsolution.

It is yet another object of the invention to provide an injectablepreparation of water-soluble salts of diclofenac, without the use ofsurfactants, and preferably, a minimized quantity of co-solvents toavoid any possible side effects.

Thus in accordance of this invention, the formulations are adjusted topH 6 to 10 containing up to 100 mg of diclofenac salt in a mediumcomprising of water, along with one or moreco-solvent(s)/solubiliser(s), antioxidants, preservatives, buffers,alkali and stabilizers.

DETAILED DESCRIPTION OF THE INVENTION

It has surprisingly been found that co-solvents/solubilisers such as ˜4%to 85% v/v of monohydric alcohol, or ˜27% to 90% v/v of polyhydricalcohol, or ˜18% to 90% v/v of tetrahydrofurfuryl propylene glycol(glycofurol), in combination with water as principal solvent allows oneto prepare injectables containing 75 mg to 100 mg of water-soluble saltsof diclofenac in ˜1 ml injection solution;

or, optionally,two or more of these co-solvents/solubilisers used in combination, up to˜80% v/v monohydric alcohol and/or up to ˜85% v/v of polyhydric alcoholand/or up to ˜85% v/v of glycofurol (tetrahydrofurfuryl propyleneglycol), along with water as principal solvent, allows one to prepareinjectables containing 75 mg to 100 mg of water-soluble salts ofdiclofenac, in about 1 ml injection solution, with reduction in theirindividual concentrations.

A injectable preparations are prepared as follows:

Diclofenac sodium is suspended in a mixture of requisite quantities ofglycofurol and say a monohydric alcohol and/or polyhydric alcohol in aninert environment, followed by addition of sterile water for injection,with stirring, followed by addition of a buffer and anti oxidant, thenadjusting the pH to 8-9 using alkali which on further dilution withsterile water for injection to achieve the required concentration of 75mg in 1 ml followed by sterilization either by sterile filtration or byautoclaving and filled in 1 ml ampoules flushed with inert gas prior tosealing. Optionally the final injectable solution is also filled in 5/10ml multi dose vials flushed with inert gas prior to sealing.

In addition to alkali metal salts of the active drug diclofenac, diethylammonium salts, and the like may also be used.

The monohydric alcohols are selected from benzyl alcohol, ethyl alcoholand the like, the polyhydric alcohols being selected from propyleneglycol and their like including polyethylene glycols with molecularweight 300 to 600 Dalton, glycerin, 1,3-butylene glycol. Preferablepolyethylene glycols include polyethylene glycol 300, polyethyleneglycol 400 and polyethylene glycol 600. The other co-solvent orsolubiliser used is glycofurol (tetrahydrofurfuryl propylene glycol).

Water-soluble salts of diclofenac are used in the range of 7.5% to 10%w/v.

The amount of monohydric alcohol, for example benzyl alcohol, when usedas the sole co-solvent/solubiliser, may be incorporated in the range ofabout 4% to 25% v/v. However when used as co-solvent/solubiliser incombination with other co-solvents the amount of benzyl alcohol is up toabout 10% v/v preferably reduced to about 4% v/v.

Polyhydric alcohol such as propylene glycol, when used as soleco-solvent/solubiliser maybe incorporated in the range of about 42% to90% v/v. However when used as co-solvents/solubilisers in combinationwith other co-solvent/solubiliser, the amount is up to about 85% v/v.

The amount of polyethylene glycols, for example polyethylene glycol 400,when used as sole co-solvent is in the range of about 27% to 90% v/v.However, when used as co-solvent/solubiliser in combination with otherco-solvent/solubilisers, the amount is up to around 85% v/v.

The amount of tetrahydrofurfuryl propylene glycol (glycofurol), whenused as sole co-solvent/solubiliser, maybe in the range of about 18 to90% v/v. However when used as a co-solvent/solubiliser with otherco-solvents/solubilisers, the amount is up to about 85% v/v.

The antioxidants are selected from sodium bisulphite, sodium metabisulphite and their like, the alkali is selected from sodium hydroxide,potassium hydroxide and their like, and the buffer system is phosphatebuffer, bicarbonate buffer and their like.

The invention is now described with a few non-limiting examples.

EXAMPLES Example 1

A parenteral preparation containing diclofenac sodium 7.5%, about 25%v/v glycofurol, about 3% v/v benzyl alcohol is prepared in an inert gasenvironment by suspending the diclofenac sodium in a mixture ofrequisite quantities of glycofurol and benzyl alcohol. Sterile water isadded with constant stirring, followed by addition of phosphate bufferand sodium bisulphite and pH adjusted to 8-9 using sodium hydroxide. Thesolution is diluted with sterile water to achieve the requiredconcentration of 75 mg in 1 ml. The entire process is carried out underinert gas environment. The ingredients may be mixed in any order. Theresultant solution is sterilized either by sterile filtration or byautoclaving and filled in 1 ml ampoules flushed with inert gas prior tosealing. The resultant solution is also filled in 5/10 ml multi dosevials flushed with inert gas prior to sealing. The viscosity of the doseis 2.64 CPS measured using Oswald U Tube viscometer. The amount ofco-solvents/solubiliser is 0.25 ml of glycofurol and 0.03 ml of benzylalcohol, totaling to 0.28 ml per injected dose. As compared to this, theviscosity of the conventional 3 ml diclofenac injections, comprising 75mg of diclofenac sodium, which contain 18 to 40% propylene glycol, is2.1 to 5.5 CPS and the quantity of co-solvent propylene glycol is 0.54ml to 1.4 ml per injected dose.

Example 2

A parenteral preparation containing diclofenac sodium 7.5% w/v. about 1%v/v of propylene glycol, 22% v/v of glycofurol, prepared as described inexample 1. The viscosity of the dose is 2.23 CPS measured using Oswald UTube viscometer. The amount of co-solvent/solubiliser is 0.01 ml ofpropylene glycol and 0.22 ml of glycofurol, totaling to 0.23 ml perinjected dose.

Example 3

A parenteral preparation containing diclofenac sodium 10% w/v, about 25%v/v glycofurol, 4% benzyl alcohol, prepared in a manner described inExample 1. The viscosity of the dose is 2.95 CPS measured using Oswald UTube viscometer. The amount of co-solvent/solubiliser is 0.25 ml ofglycofurol and 0.04 ml of benzyl alcohol, totaling to 0.29 ml perinjected dose.

Example 4

A parenteral preparation containing diclofenac sodium 7.5% w/v, about13% v/v glycofurol, 4% benzyl alcohol, prepared in a manner described inExample 1. The final dosage contains. The viscosity of the dose is 1.69CPS measured using Oswald U Tube viscometer. The amount ofco-solvent/solubiliser is 0.13 ml of glycofurol and 0.04 ml of benzylalcohol, totaling to 0.17 ml per injected dose.

Example 5

A parenteral preparation containing diclofenac potassium 7.88% w/v.about 4% v/v of benzyl alcohol, 13% v/v of glycofurol, prepared asdescribed in example 1. The viscosity of the dose is 1.72 CPS measuredusing Oswald U Tube viscometer. The amount of co-solvent/solubiliser is0.04 ml of benzyl alcohol and 0.13 ml of glycofurol, totaling to 0.17 mlper injected dose.

Example 6

A parenteral preparation containing diclofenac diethyl ammonium 8.7%w/v. about 4% v/v of benzyl alcohol, 5% v/v of glycofurol, prepared asdescribed in example 1. The viscosity of the dose is 1.57 CPS measuredusing Oswald U Tube viscometer. The amount of co-solvent/solubiliser is0.04 ml of benzyl alcohol and 0.05 ml of glycofurol, totaling to 0.09 mlper injected dose.

Example 7

A parenteral preparation containing diclofenac diethyl ammonium 8.7%w/v. about 4% v/v of benzyl alcohol, 2% v/v of glycofurol, 1% propyleneglycol, prepared as described in example 1. The viscosity of the dose is1.59 CPS measured using Oswald U Tube viscometer. The total amount ofco-solvent/solubiliser is 0.04 ml of benzyl alcohol, 0.02 ml ofglycofurol and 0.01 ml of propylene glycol, totaling to 0.07 ml perinjected dose.

Example 8

A parenteral preparation containing diclofenac sodium 7.5% w/v. about35% v/v of glycofurol, prepared as described in example 1. The viscosityof the dose is 3.99 CPS measured using Oswald U Tube viscometer. Thetotal amount of co-solvent/solubiliser is 0.35 ml per injected dose. Inview of the fact that the concentration of the injection solution isthree times that of the generally used concentration, sub-acute toxicitystudy was performed to ascertain that the injection solution was devoidof toxicity.

Example 9

A parenteral preparation containing diclofenac sodium 7.5% w/v. about45% v/v of propylene glycol, prepared as described in example 1. Theviscosity of the dose is 4.38 CPS measured using Oswald U Tubeviscometer. The total amount of co-solvent/solubiliser is 0.45 ml of perinjected dose

Example 10

A parenteral preparation containing diclofenac sodium 7.5% w/v. about33% v/v of polyethylene glycol 400, prepared as described in example 1.The viscosity of the dose is 4.69 CPS measured using Oswald U Tubeviscometer. The total amount of co-solvent/solubiliser is 0.35 ml perinjected dose

In view of the fact that the concentration of the injection solution isthree times that of the generally used concentration, sub-acute toxicitystudy was performed to ascertain that the injection solution was devoidof toxicity

Sub-acute toxicity studies of diclofenac sodium 75 mg/ml injection for 4weeks with weekly observations were performed at The L.M. College ofPharmacy, Department of Pharmacology, Ahmedabad, India. The dose asprepared in example 4 was chosen for the study. 16 Healthy albinorabbits (8 males & 8 females) and 48 Healthy Wistar rats (24 males & 24females) were chosen for the study. All animals were kept in isolatedcages in air-conditioned animal house with standard light, humidity,diet and water supply

Four groups 4×2 (each of six rats) and 4×2 (each of 2 rabbits) werecreated for the study.

Group 1 consisting of 6 male and 6 female rats was intravenouslyadministered normal saline injections of volume of 0.1 ml/100 g bodyweight and for the 6 male and 6 female rabbits volume of 0.1 m/kgbody-weight.

Group 2 consisting of 6 male and 6 female rats and 6 male and 6 femalerabbits was administered 75 mg/m Diclofenac sodium equivalenttherapeutic intravenously in human dose i.e 1.0 mg/kg body weight

Group 3 consisting of 6 male and 6 female rats and 6 male and 6 femalerabbits was administered 75 mg/ml Diclofenac sodium equivalenttherapeutic intravenously in human dose i.e 5.0 mg/kg body weight

Group 4 consisting of 6 male and 6 female rats and 6 male and 6 femalerabbits was administered 75 mg/ml Diclofenac sodium equivalenttherapeutic intravenously in human dose i.e 10.0 mg/kg body weight

Body weight, Food consumption, Water intake, including Generalexamination and Biochemical Investigations such as Complete blood count,Serum Cholesterol, Serum Glucose, SGOT & SGPT, Serum Urea and SerumCreatinine were monitored weekly,

There was no significant difference in the growth or in the final bodyweight attained in all four test groups as compared to control (FIG.1,2). Food intake was adequate indicating no change in the appetite(FIG. 3,4). Water intake was also not significantly different in testanimals as compared to control (FIG. 5,6). Activity of animals wasnormal and there were no apparent features of stimulation or depressionnoted.

Serum glucose, serum cholesterol, serum GOT., serum GPT or serum urealevels measured in rats and rabbits were not found to be significantlyaltered in any of the test groups as compared to control. Serumcreatinine was also not altered in any group except in rats treated with10 mg/kg. This dose did not produce any significant change in creatininelevels in rabbits. Histopathological examination of all the organs andthe microscopic examination of liver, kidney, lung and heart did notreveal any apparent change except for degenerative changes observed inliver obtained from rabbit treated with 5 mg/kg and 10 mg/kg diclofenacsodium. The changes in liver have already been reported for diclofenacper se (Helfgott et al. 1990. JAMA, 264:20; Roque et al. 1999.Pharmacol. Experimental Thera, 288: 65-72.). The adjuvants used in theformulations do not be produce any toxic effect in the animals studied.

The study suggests that treatment of diclofenac sodium injection has noundue toxicity as compared to the negative control.

1. Injectable preparations of viscosity ranging from about 1.50 to 4.7CPS and pH of ˜8-9, containing 75 mg/ml of diclofenac sodium or itstherapeutically equivalent amounts of water-soluble salts of diclofenac,comprising, cosolvents/solubilisers such as a monohydric alcohol ˜4% to25% % v/v, or a polyhydric alcohol ˜27% to 45% v/v, ortetrahydrofurfuryl alcohol propylene glycol ether (glycofurol) ˜18% to35% v/v, in combination with water, or, a solvent system comprising ofcombinations of at least two or more co-solvents/solubilisers selectedfrom differing classes, wherein the monohydric alcohol(s) are up to ˜15%v/v, preferably 4%-8%, polyhydric alcohol(s) are up to ˜25% v/v,preferably 15%, tetrahydrofurfuryl alcohol propylene glycol ether(glycofurol) up to ˜25% v/v preferably up to 15%; with water, such thatthe total quantum of co-solvent/solubilisers does not exceed 35% v/v ofthe composition.
 2. Injectable preparations of viscosity ranging fromabout 2.60 to 3.50 CPS and pH of ˜8-9 containing 100 mg/ml of diclofenacsodium or its therapeutically equivalent amounts of water-soluble saltsof diclofenac in a solvent system comprising of combinations of at leasttwo or more co-solvents/solubilisers selected from differing classes,wherein the monohydric alcohol(s) is up to ˜15% v/v, preferably 4-8%,polyhydric alcohol(s) is up to ˜25% v/v, preferably up to 15%,tetrahydrofurfuryl alcohol propylene glycol ether (glycofurol) ˜25% v/vof preferably up to ˜15%; with water as principal solvent, such that thetotal quantum of co-solvent/solubilisers does not exceed 35% v/v of thecomposition.
 3. Injectable preparations of diclofenac and itspharmaceutically accepted salts as high concentration preparations asclaimed in claims 1-2, wherein the said diclofenac salt is selected fromalkali metal salts, diethyl ammonium salts.
 4. Injectable preparationsof diclofenac and its pharmaceutically accepted salts as highconcentration preparations as claimed in claims 1-3, wherein theco-solvents/solubilisers are selected from differing classes ofmonohydric alcohols such as benzyl alcohol, ethyl alcohol, polyhydricalcohols such as propylene glycol, polyethylene glycols with molecularweight 300 to 600 Dalton, glycerin and 1,3-butylene glycol. 5.Injectable preparations of diclofenac and its pharmaceutically acceptedsalts as high concentration preparations as claimed in claims 1-4,wherein the polyhydric alcohol is polyethylene glycol 300, polyethyleneglycol 400, polyethylene glycol
 600. 6. Injectable preparations ofdiclofenac and its pharmaceutically accepted salts wherein, highconcentration preparations as claimed in claims 1-5, wherein benzylalcohol, when used as the sole co-solvent/solubiliser for 75 mg/mlconcentration of diclofenac sodium or its therapeutically equivalentamounts of water-soluble salts of diclofenac, is incorporated at ˜4% to25% v/v.
 7. Injectable preparations of diclofenac and itspharmaceutically accepted salts wherein, high concentration preparationsas claimed in claims 1-6, wherein benzyl alcohol when used asco-solvent/co-solubiliser in combination with other co-solvents, for the75 mg/ml concentration of diclofenac sodium or its therapeuticallyequivalent amounts of water-soluble salts of diclofenac, as well as forthe 100 mg/ml concentration of diclofenac sodium or its therapeuticallyequivalent amounts of water-soluble salts of diclofenac, the amount ofbenzyl alcohol used is up to about 15% v/v preferably reduced to about4-8% v/v.
 8. Injectable preparations of diclofenac and itspharmaceutically accepted salts as high concentration preparations asclaimed in claims 1-7, wherein polyhydric alcohol such as propyleneglycol, when used as sole co-solvent/solubiliser for 75 mg/mlconcentration of diclofenac sodium or its therapeutically equivalentamounts of water-soluble salts of diclofenac, is in the range of ˜27%v/v to ˜45% v/v.
 9. Injectable preparations of diclofenac and itspharmaceutically accepted salts as high concentration preparations asclaimed in claim 8, wherein polyhydric alcohol is polyethylene glycol400.
 10. Injectable preparations of diclofenac and its pharmaceuticallyaccepted salts as high concentration preparations as claimed in claims1-8, wherein polyhydric alcohol such as propylene glycol, polyethyleneglycol 400 when used as co-solvent/solubiliser in combination with otherco-solvents/solubilisers, for 75 mg/ml concentration of diclofenacsodium or its therapeutically equivalent amounts of water-soluble saltsof diclofenac as well as for the 100 mg/ml concentration of diclofenacsodium or its therapeutically equivalent amounts of water-soluble saltsof diclofenac, the amount is up to ˜25 v/v % v/v, preferably ˜15% v/v.11. Injectable preparations of diclofenac and its pharmaceuticallyaccepted salts as high concentration preparations as claimed in claims1-7, wherein tetrahydrofurfuryl propylene glycol (glycofurol), when usedas sole co-solvent/solubiliser, for 75 mg/ml concentration of diclofenacsodium or its therapeutically equivalent amounts of water-soluble saltsof diclofenac, maybe in the range of ˜18-35% v/v.
 12. Injectablepreparations of diclofenac and its pharmaceutically accepted salts ashigh concentration preparations as claimed in claims 1-7, and 11 whereintetrahydrofurfuryl propylene glycol (glycofurol) when used as aco-solvent/solubiliser with other co-solvents/solubilisers, for 75 mg/mlconcentration of diclofenac sodium or its therapeutically equivalentamounts of water-soluble salts of diclofenac as well as for the 100mg/ml concentration of diclofenac sodium or its therapeuticallyequivalent amounts of water-soluble salts of diclofenac, the amount isup to about 25 v/v %, preferably up to ˜15% v/v.
 13. A process for thepreparation of injectable preparations of diclofenac and itspharmaceutically accepted salts as high concentration preparations of ˜1ml injection solution containing 75 mg as claimed in claim 1, whereinthe water-soluble diclofenac salt is suspended in requisite quantitiesof either monohydric alcohol or polyhydric alcohol, ortetrahydrofurfuryl alcohol propylene glycol ether (glycofurol), underinert conditions, to which sterile water for injection is added withstirring maintaining inert conditions, followed by addition of bufferand anti oxidant, adjusting the pH between 8-0.9 using alkali, thendiluting with sterile water for injection, to achieve concentration of˜75 mg in 1 ml.
 14. A process for the preparation of injectablepreparations of diclofenac and its pharmaceutically accepted salts ashigh concentration preparations of ˜1 ml injection solution containing75 mg as claimed in claim 1, wherein the water soluble diclofenac saltis suspended in a mixture comprising a combination of requisitequantities of two or three of co-solvents/solubilisers selected frommonohydric alcohol/s and/or polyhydric alcohol/s, and/ortetrahydrofurfuryl alcohol propylene glycol ether (glycofurol), underinert conditions to which sterile water for injection is added withstirring maintaining inert conditions, followed by addition of bufferand antioxidant, adjusting the pH between 8-9 using alkali, followed bydiluting with sterile water for injection to achieve the concentrationof ˜75 mg in 1 ml.
 15. A process for the preparation of injectablepreparations of diclofenac and its pharmaceutically accepted salts ashigh concentration preparations of ˜1 ml injection solution containing100 mg as claimed in claim 2, wherein the water soluble diclofenac saltis suspended in a judiciously chosen solvent mixture comprising acombination of requisite quantities of two or all three ofco-solvents/solubilisers selected from monohydric alcohol/s and orpolyhydric alcohol/s, and/or tetrahydrofurfuryl alcohol propylene glycolether (glycofurol), under constant nitrogen bubbling to which sterilewater for injection is added with stirring and nitrogen bubbling,followed by addition of buffer and antioxidant, adjusting the pH between8-9 using alkali, then diluting with sterile water for injection toachieve concentration of ˜100 mg in 1 ml.
 16. A process for thepreparation of Injectable preparations of diclofenac and itspharmaceutically accepted salts as high concentration preparations asclaimed in claims 1-16, wherein the antioxidant is selected sodium saltssuch as sodium bisulphite, sodium meta bisulphate. the alkali isselected from hydroxides such as sodium hydroxide, potassium hydroxide,and the buffer system is a phosphate buffer, bicarbonate buffer.